MeCP2 EXPRESSION CASSETTES

Abstract

MeCP2 expression cassettes. The present invention provides nucleic acid molecules comprising a MeCP2 expression cassette, the expression cassette comprising, in operable linkage from 5' to 3': a 5' transcriptional control region comprising a promoter capable of driving transcription in neural cells; an open reading frame encoding a MeCP2 protein; translation control signals; a 3' untranslated region (3'UTR) comprising one or more of: (i) a binding site for mir-22; (ii) a binding site for mir-19; (iii) a binding site for miR-132; (iv) a binding site for miR124; and (v) an AU-rich element; and transcriptional termination signals; wherein the MeCP2 expression cassette is not more than about 5 kb in length. The invention further provides viral vectors, especially vectors derived from adeno-associated virus (AAV), for use in therapeutic delivery of such expression cassettes. The nucleic acid molecules and viral vectors disclosed herein provide novel tools for expressing MeCP2 and are of particular value in the treatment of disorders associated with reduced MeCP2 activity, including Rett syndrome.

Description

Technical field [0001] The present invention relates to an expression cassette containing a gene encoding MeCP2 protein, and to viral vectors, particularly vectors derived from adeno-associated virus (AAV), which are used for the therapeutic delivery of such expression cassettes. Background technique [0002] Rett syndrome (RTT; OMIM 312750) is a neurological disease characterized by a series of clinical diagnoses and related features, and obvious attacks appear several months after birth 1 . The typical RTT is almost entirely caused by a new germline mutation in the X-linked gene MECP2 2 ; For review see 3,4 . Several types of missing Mecp2 have been generated 5-7 Or type 8-11 Mutant RTT mouse model. Many of these models recapitulate the main characteristics that characterize human RTT, although some differences reflect the phenotypic variability of patients 12-14 . Regardless of the severity of the RTT-like phenotype, the reactivation of the silenced Mecp2 gene in conditional...

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Problems solved by technology

However, gene transfer methods face significant challenges, including the need to transduce sufficient numbers of neurons in the brain 16 , and to avoid deleterious overexpression of 18

[0004] Previous Attempts to Use AAV9 Vectors for MECP2 Gene Transfer Disrupted by Limited Brain Transduction Efficiency and Toxicity 19,20 , while other studies using self-complementing AAV (scAAV) 21 Efficacy in may be compromised by using constructs that exceed the packaging capacity of the vector

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